Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. In 2012, cancer occurred in about 14.1 million people. It caused about 8.2 million deaths or 14.6% of all human deaths. The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer. In females the most common types are breast cancer, colorectal cancer, and lung cancer, and cervical cancer.
The epidermal growth factor receptor (EGFR), also known as ErbB-1 or HER1 in humans, is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. EGFR is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4).
Mutations affecting EGFR expression or activity could result in cancer. In particular, mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers (such as colorectal cancer) and glioblastoma multiforme. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division. In glioblastoma a more or less specific mutation of EGFR, called EGFRvIII is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
An innovative approach to cancer treatment was disclosed in WO 2005/079423 which describes an immunity linker which contains two binding moieties. The first binding moiety is capable of binding to an immune response component of an individual. The second binding moiety is capable of binding to any compound or foreign material such as antigens, pathogens, chemicals, or endogenous materials such as altered cells found in cancer. The resultant effect of said immunity linker molecule is that the immune response of the individual is diverted from the pre-existing immune response of said individual towards the target, i.e. the cancer cell. Examples of said first binding moieties include compounds or agents which are recognised by the immune system of said individual as foreign and which would therefore trigger an immune response. One such example is the alpha-Gal epitope (i.e. galactosyl-alpha-1,3-galactosyl-beta-1,4-N-acetylglucosamine) which results in redirection of the natural human serum antibody Anti-alpha-galactosyl. Examples of said second binding moieties include antibodies and aptamers. Aptamers are oligonucleic acid or peptide molecules that bind to a specific target molecule. The principle of the method disclosed in WO 2005/079423 is that the second binding moiety (i.e. aptamer) of the linker molecule will bind to an epitope on a cancer cell and the presence of the first binding moiety (i.e. the alpha-Gal epitope) on the linker molecule will divert an immune response to the cancer cell resulting in effective destruction of the cancer cell.
Li et al (2011) PLoS One 6(6), 1-9 describes a series of anti-EGFR aptamers, including E07. A dissertion was presented by Viswatej Avutu in 2011 (repositories.lib.utexas.edu/bitstream/handle/2152/13407/Avutu-Bioch 10.pdf?sequence=2) which describes a minimised variant of E07 known as MinE07 which has the following sequence:
5′-rGrGrA fCrGrG rAfUfU fUrArA fUfCrG fCfCrG fUrArG rArArA rArGfC rAfUrG fUfCrA rArArG fCfCrG rGrArA fCfCrG fUfCfC-3′ (SEQ ID NO: 85), wherein “r” represents a natural 2′-OH (RNA) nucleotide and “f” represents a modified 2′-fluoro nucleotide. In this sequence there are 28 of 48 unmodified nucleotides which can lead to nuclease degradation when administered therapeutically.
There is therefore, a great need for alternative, therapeutically effective aptamers which not only retain the ability to bind to epitopes present on cancer cells, but which are also capable of withstanding degradation. Such aptamers will have great utility in binding complexes with agents capable of binding to an immune response component of an individual to provide effective anti-cancer therapies.